Process for preparing cephem compounds

ABSTRACT

The present invention provides a process for preparing a cephem compound represented by the general formula (3) characterized in that an allenyl-β-lactam compound represented by the general formula (1) is reacted with an organotin compound represented by the general formula (2) in the presence of a monovalent copper salt ##STR1## wherein R 1  is a hydrogen atom, halogen atom, amino or protected amino, R 2  is a hydrogen atom, halogen atom, lower alkoxyl, lower acyl, lower alkyl, lower alkyl having hydroxyl or protected hydroxyl as a substituent, hydroxyl or protected hydroxyl, or R 1  and R 2  form=0 when taken together, R 3  is a hydrogen atom or carboxylic acid protecting group, R 4  is aryl, aryl having a substituent, nitrogen-containing aromatic heterocyclic group or nitrogen-containing aromatic heterocyclic group having a substituent, and m is 0 or 2, 
     
         (R.sup.5).sub.n --Sn(R.sup.6).sub.4--n                     (2) 
    
     wherein R 5  is alkenyl, alkenyl having a substituent, aryl, aryl having a substituent, nitrogen-containing aromatic heterocyclic group or nitrogen-containing aromatic heterocyclic group having a substituent, R 6  is lower alkyl, and n is 1 or 2, ##STR2## wherein R 1 , R 2 , R 3  and R 5  are the same as defined above.

This is a national phase application filed under 37 C.F.R. 371 ofPCT/JP93/01041 filed Jul. 26, 1993.

TECHNICAL FIELD

The present invention relates to a process for preparing cephemcompounds having a broad antibacterial spectrum.

BACKGROUND ART

The Witting reaction is already known as a process for preparing3-alkenyl cephem compounds (e.g., JP-A-120288/1991, JP-A-307885/1988,etc.).

Also known as a process for preparing 3-alkenyl, 3-aryl and3-heterocyclic cephem compounds is the process wherein a cephem compoundhaving an elimination group L (such as fluorosulfonyloxy group ortrifluoromethylsulfonyloxy group) at the C(3)- position is reacted withan organotin compound in the presence of a palladium catalyst(JP-A-220195/1991 and JP-A-313483/1989).

These processes each use a compound having a cephem skeleton as thestarting material and have problems, for example, in respect of theeconomy of the material or the number of steps involved in preparing thematerial.

Further a report was recently made on a process for preparing 3-alkenylor 3-aryl cephem compounds, i.e., a process wherein an allenyl-β-lactamcompound found by us (Torii et al., Synlett, 1991, 888), represented bythe general formula (1) and serving as the starting material is reactedwith an organocopper reagent prepared in advance from an organotincompound and dimethyl cuprate, or an organolithium compound and cuprousiodide, or a Grignard reagent and cuprous iodide [Kant et al.,Tetrahedron Letters, 33 (25), 3563 (1992)]. This process affords thedesired cephem compound from an inexpensive penicillin compound by ashort reaction step. With this process, however, the reaction must beconducted at an extremely low temperature (-100° to -78° C. ) which isindustrially infeasible, further produces an undesirable 2-cephemcompound as a by-product and encounters difficulty in purifying thedesired product.

An object of the present invention is to provide a novel process forpreparing various cephem compounds having a broad antibacterial spectrumfrom an allenyl-β-lactam compound easily by a simplified reactionprocedure under reaction conditions which can be industrially realizedwith ease, the lactam compound being readily available from aninexpensive penicillin compound by a short reaction step.

The present invention provides a process for preparing a cephem compoundrepresented by the general formula (3) characterized in that anallenyl-β-lactam compound represented by the general formula (1) isreacted with an organotin compound represented by the general formula(2) in the presence of a monovalent copper salt ##STR3## wherein R¹ is ahydrogen atom, halogen atom, amino or protected amino, R² is a hydrogenatom, halogen atom, lower alkoxyl, lower acyl, lower alkyl, lower alkylhaving hydroxyl or protected hydroxyl as a substituent, hydroxyl orprotected hydroxyl, or R¹ and R² form=0 when taken together, R³ is ahydrogen atom or carboxylic acid protecting group, R⁴ is aryl, arylhaving a substituent, nitrogen-containing aromatic heterocyclic group ornitrogen-containing aromatic heterocyclic group having a substituent,and m is 0 or 2,

    (R.sup.5).sub.n --Sn(R.sup.6).sub.4--n                     ( 2)

wherein R⁵ is alkenyl, alkenyl having a substituent, aryl, aryl having asubstituent, nitrogen-containing aromatic heterocyclic group ornitrogen-containing aromatic heterocyclic group having a substituent, R⁶is lower alkyl, and n is 1 or 2, ##STR4## wherein R¹, R², R³ and R⁵ arethe same as defined above.

Examples of groups mentioned herein are as follows. The term "halogenatom" as used hereinafter means, for example, fluorine, chlorine,bromine or iodine atom unless otherwise specified. The term "loweralkyl" means a straight-chain or branched C₁˜4 alkyl group such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl ortert-butyl. The term "aryl" means, for example, phenyl, naphthyl or thelike.

Exemplary of the protected amino represented by R¹ are phenoxyacetamido,p-methylphenoxyacetamido, p-methoxyphenoxyacetamido,p-chlorophenoxyacetamido, p-bromophenoxyacetamido, phenylacetamido,p-methylphenylacetamido, p-methoxyphenylacetamido,p-chlorophenylacetamido, p-bromophenylacetamido,phenylmonochloroacetamido, phenyldichloroacetamido,phenylhydroxyacetamido, phenylacetoxyacetamido, α-oxophenylacetamido,thienylacetamido, benzamido, p-methylbenzamido, p-tert-butylbenzamido,p-methoxybenzamido, p-chlorobenzamido and p-bromobenzamido groups, thegroups disclosed in Theodora W. Greene, "Protective Groups in OrganicSynthesis" (hereinafter referred to merely as the "literature"), Chap. 7(pp. 218˜287), phenylglycylamido group, phenylglycylamido groups havingprotected amino, p-hydroxyphenylglycylamido group, andp-hydroxyphenylglycylamido groups having protected amino and/orprotected hydroxyl. Examples of protective groups for amino are thosedisclosed in the literature, Chap. 7 (pp. 218˜287). Examples ofprotective groups for the hydroxyl of p-hydroxyphenylglycylamido groupare those disclosed in the literature, Chap.2 (pp. 10˜72).

Exemplary of the lower alkoxyl represented by R² are straight-chain orbranched C₁˜4 alkoxyl groups such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy groups.

Exemplary of the lower acyl represented by R² are straight-chain orbranched C₁˜4 acyl groups such as formyl, acetyl, propionyl, butyryl andisobutyryl.

Examples of protective groups for the protected hydroxyl in the loweralkyl represented by R² and substituted with hydroxyl or protectedhydroxyl, and for the protected hydroxyl represented by R² are thosedisclosed in the literature, Chap. 2 (pp. 10˜72). The substituted loweralkyl represented by R² may have as its substituent(s) one or at leasttwo same or different groups selected from among hydroxyl and theprotected hydroxyl groups. Such substituent(s) may be positioned on atleast one carbon atom of the alkyl.

Exemplary of the carboxylic acid protecting group represented by R³ arebenzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, trichloroethyl,tert-butyl, and those disclosed in the literature, Chap. 5 (pp.152˜192).

While R⁴ represents a nitrogen-containing aromatic heterocyclic groupwhich may have a substituent or substituents, exemplary of thenitrogen-containing aromatic hetrocyclic group are thiazol-2-yl,thiadiazol-2-yl, benzothiazol-2-yl, oxazol-2-yl, benzoxazol-2-yl,imidazol-2-yl, benzoimidazol-2-yl, pyrimidinyl, pyridyl and the like.

Exemplary of the substituent which may be substituted in the aryl ornitrogen-containing aromatic heterocyclic group represented by R⁴ arehalogen atoms, hydroxyl, nitro, cyano, aryl, lower alkyl, amino, monolower alkylamino, di lower alkylamino, mercapto, alkylthio or arylthiorepresented by the group R⁷ S-- (wherein R⁷ is lower alkyl or aryl),formyloxy, acyloxy represented by the group R⁷ COO-- (wherein R⁷ is asdefined above), formyl, acyl represented by the group R⁷ CO-- (whereinR⁷ is as defined above), alkoxyl or aryloxy represented by R⁷ O--(wherein R⁷ is as defined above), carboxyl, alkoxycarbonyl oraryloxycarbonyl represented by the group R⁷ OCO-- (wherein R⁷ is asdefined above), etc. The aryl or nitrogen-containing aromaticheterocyclic group represented by R⁴ may have one or at least two sameor different groups selected from among the above substituents.

Examples of the alkenyl represented by R⁵ are vinyl, 1-propenyl,propene-2-yl, 2-methylpropene-1-yl, (E)-1-styryl, trifluorovinyl,1-methoxypropene-1-yl, 1-cyclohexenyl, 4-tert-butylcyclohexen-1-yl,(E)-2-tributylstannylvinyl, allenyl, 1-butene-1-yl and the like.Examples of the nitrogen-containing aromatic heterocyclic groups arepyridyl, pyrazyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl,pyrazolyl, isothiazolyl, isooxazolyl, purinyl, pteridinyl and the like.

R⁵ represents alkenyl, aryl or nitrogen-containing aromatic heterocyclicgroup which may have a substituent or substituents, examples of whichare those mentioned for R⁴. The alkenyl, aryl or nitrogen-containingaromatic heterocyclic group represented by R⁵ may have one or at leasttwo same or different groups selected from among the foregoingsubstituents.

The allenyl-β-lactam compound of the formula (1) for use as the startingmaterial of the present invention is prepared, for example, by theprocess disclosed in literature (Torii et al., Synlett, 1991, 888) (seeReference Examples given later).

According to the invention, the allenyl-β-lactam compound represented bythe formula (1) and prepared by the above process is reacted with anorganotin compound represented by the formula (2) in the presence of amonovalent copper salt, whereby a cephem compound represented by theformula (3) is obtained.

More specific examples of organotin compounds represented by the formula(2) are vinyltributyltin, divinyldibutyltin, (Z)-1-propenyltributyltin,(E)-1-styryltributyltin, 1-tributylstannyl-1-methylpropene,1-tributylstannyl-2-methylpropene, (trifluorovinyl)tributyltin,1-methoxy-1-(tributylstannyl)ethylene, 1-tributylstannyl-cyclohexene,(4-tert-butylcyclohexen-1-yl)trimethyltin,(4-tert-butylcylcohexen-1-yl)tributyltin,(E)-1,2-bis(tributylstannyl)ethylene, allenyltributyltin,1-tributylstannyl-1-butene, phenyltributyltin,(p-methoxyphenyl)tributyltin, [p-(trifluoromethyl)phenyl]-tributyltin,2-tributylstannylpyridine, 2-tributylstannyl-pyrazine,2-tributylstannylpyrimidine, 3-tributylstannyl-pyridazine,1-methyl-2-(tributylstannyl)pyrrole,1-methyl-2-(tributylstannyl)imidazole,1-methyl-3-(tributylstannyl)-pyrazole, 3-tributylstannylisothiazole,3-tributylstannyl-isooxazole, 7-methyl-8-tributylstannylpurine,2-tributylstannylpteridine and the like. These organotin compoundsrepresented by the formula (2) are used usually in an amount of 1 to 3moles, preferably 1 to 2 moles, per mole of the compound of the formula(1).

Examples of monovalent copper salts are cuprous halides such as cuprouschloride, cuprous bromide and cuprous iodide, etc. These copper saltsare used in an amount of 0.5 to 10 moles, preferably 1 to 3 moles, permole of the compound of the formula (1).

Examples of solvents are dimethylacetamide, dimethylformamide,1-methyl-2-pyrrolidinone, hexamethyl phosphoric triamide and likeamides, acetonitrile, propionitrile, butyronitrile, isobutyronitrile,valeronitrile and like nitriles, dimethyl sulfoxide, etc. These solventsmay be used singly, or at least two of them may be used in admixture.Also usable are solvent mixtures consisting primarily of such a solventand further comprising other usual solvents, which are, for example,lower alkyl esters of lower carboxylic acids such as methyl formate,ethyl formate, propyl formate, butyl formate, methyl acetate, ethylacetate, propyl acetate, butyl acetate, methyl propionate and ethylpropionate, ethers such as diethyl ether, ethyl propyl ether, ethylbutyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methylcellosolve and dimethoxyethane, cyclic ethers such as tetrahydrofuranand dioxane, substituted or unsubstituted aromatic hydrocarbons such asbenzene, toluene, xylene, chlorobenzene and anisole, hydrocarbon halidessuch as dichloromethane, chloroform, dichloroethane, trichloroethane,dibromoethane, propylene dichloride, carbon tetrachloride and Freons,hydrocarbons such as pentane, hexane, heptane and octane, andcycloalkanes such as cyclopentane, cyclohexane, cycloheptane andcyclooctane. Especially preferred solvents are solvent mixturesconsisting primarily of dimethylformamide, 1-methyl-2-pyrrolidinone ordimethyl sulfoxide. These solvents are used in an amount of about 0.5 toabout 200 liters, preferably about 1 to about 50 liters, per kilogram ofthe compound of the formula (1). The reaction is conducted at -10° C. to80° C., preferably 0° C. to 50° C. The compound of the present inventioncan be obtained in the form of a substantially pure product bysubjecting the resulting reaction mixture to extraction orcrystallization in the usual manner, while the product can of course bepurified by other method.

BEST MODE OF CARRYING OUT THE INVENTION

The present invention will be clarified in greater detail with referenceto the following examples. Ph stands for phenyl.

EXAMPLE 1 p-Methoxybenzyl 7-phenylacetamido-3-vinylcephalosporanate

A 100 mg quantity of a compound of the formula (1) (R¹ =phenylacetamido,R² =H, R³ =p-methoxybenzyl, R⁴ =phenyl, m=2, 1a) and 20.5 mg of cuprouschloride were weighed out, to which 1 ml of 1-methyl-2-pyrrolidinone wasadded. With addition of 76 μl of vinyltributyltin, the mixture wasstirred at room temperature for reaction. Ethyl acetate and 2%hydrochloric acid were added to the reaction mixture for extraction, andthe resulting organic layer was washed with water and a common saltaqueous solution. The organic layer was dried over sodium sulfate anddistilled at a reduced pressure to remove the solvent, affordingcrystals. When purified with a silica gel column (benzene/ethylacetate=6/1), the crude crystals gave 72.3 mg (yield 90%) of a compoundof the formula (3) (R¹ =phenylacetamido, R² =H, R³ =p-methoxybenzyl, R⁵=vinyl, 3a)

EXAMPLE 2

The same reaction as in Example 1 was repeated using cuprous bromideinstead of cuprous chloride, whereby the corresponding compound 3a ofthe formula (3) was obtained in a yield of 87%.

EXAMPLE 3

The same reaction as in Example 1 was conducted using cuprous iodideinstead of cuprous chloride, whereby the corresponding compound 3a ofthe formula (3) was obtained in a yield of 80%.

EXAMPLE 4

The same reaction as in Example 1 was conducted usingN,N-dimethylformamide instead of 1-methyl-2-pyrrolidinone, whereby thecorresponding compound 3a of the formula (3) was obtained in a yield of82%.

EXAMPLE 5

The same reaction as in Example 1 was conducted using a compound of theformula (1) (R¹ =phenylacetamido, R² =H, R³ =p-methoxybenzyl, R⁴=benzothiazol-2-yl, m=0, 1b) instead of the compound of the formula (1)(R¹ =phenylacetamido, R² =H, R³ =p-methoxybenzyl, R⁴ =phenyl, m=2, 1a),whereby the corresponding compound 3a of the formula (3) was obtained ina yield of 82%.

EXAMPLES 6 to 11

The same reaction as in Example 1 was conducted using the compound ofthe formula (1) (R¹ =phenylacetamido, R² =H, R³ =p-methoxybenzyl, R⁴=phenyl, m=2, 1a) and a compound represented by the formula (2) (R⁶=butyl, n=1) and having a substituent shown in Table 1 as R⁵, wherebythe corresponding compound of the formula (3) (R¹ =phenylacetamido, R²=H, R³ =p-methoxybenzyl, see Table 1 for R⁵) was obtained.

                  TABLE 1                                                         ______________________________________                                        Example    R.sup.5         yield of compound (3)                              ______________________________________                                        6          propene-2-yl    91%    3b                                          7          (Z)-1-propenyl  89%    3c                                          8          2-methylpropene-1-yl                                                                          89%    3d                                          9          allenyl         80%    3e                                          10         phenyl          85%    3f                                          11         (E)-1-styryl    73%    3g                                          ______________________________________                                    

EXAMPLES 12 to 26

The same reaction as in Example 1 was conducted using a compound of theformula (1) (see Table 2 for R¹ and R³, R² =H, R⁴ =phenyl, m=2) and acompound represented by the formula (2) (R⁶ =butyl, n=1) and having asubstituent shown in Table 2 as R⁵, whereby the corresponding compoundof the formula (3) (see Table 2 for R¹, R³ and R⁵, R² =H) was obtained.

                  TABLE 2                                                         ______________________________________                                                                               yield                                  Ex.  R.sup.1      R.sup.3     R.sup.5  (%)                                    ______________________________________                                        12   phenylacetamido                                                                            diphenylmethyl                                                                            (Z)-1-propenyl                                                                         88                                     13   phenylacetamido                                                                            diphenylmethyl                                                                            allenyl  81                                     14   phenylacetamido                                                                            diphenylmethyl                                                                            phenyl   83                                     15   phenylacetamido                                                                            p-nitrobenzyl                                                                             (Z)-1-propenyl                                                                         89                                     16   phenylacetamido                                                                            p-nitrobenzyl                                                                             allenyl  78                                     17   phenylacetamido                                                                            p-methoxybenzyl                                                                           (Z)-1-propenyl                                                                         90                                     18   phenylacetamido                                                                            p-methoxybenzyl                                                                           allenyl  82                                     19   phenylacetamido                                                                            p-methoxybenzyl                                                                           phenyl   85                                     20   phenylacetamido                                                                            diphenylmethyl                                                                            (Z)-1-propenyl                                                                         89                                     21   phenylacetamido                                                                            p-nitrobenzyl                                                                             (Z)-1-propenyl                                                                         90                                     22   phenylacetamido                                                                            p-nitrobenzyl                                                                             allenyl  80                                     23   H            p-methoxybenzyl                                                                           (Z)-1-propenyl                                                                         92                                     24   H            p-methoxybenzyl                                                                           allenyl  83                                     25   H            diphenylmethyl                                                                            (Z)-1-propenyl                                                                         90                                     26   H            diphenylmethyl                                                                            allenyl  81                                     ______________________________________                                    

REFERENCE EXAMPLE 1

Preparation of allenyl-βlactam of formula (1) ##STR5##

One gram of a compound of the formula (4) (R¹ =phenylacetamido, R² =H,R³ =p-methoxybenzyl, R⁴ =phenyl, R⁸ =trifluoromethyl, m=2) was dissolvedin 10 ml of N,N-dimethylformamide. The solution was cooled to -30° C.,and 0.43 ml of triethylamine was thereafter added to the solution,followed by stirring at the same temperature for 1 hour. The reactionmixture was subjected to extraction with ethyl acetate, and the extractwas washed with water and thereafter dried over anhydrous sodiumsulfate. When concentrated at a reduced pressure, the extract gave thecorresponding compound of the formula (1) (R¹, R², R³, R⁴ and m are asdefined above, 1a) in a yield of 99%.

REFERENCE EXAMPLE 2

The same reaction as in Reference Example 1 was conducted using anothercompound of the formula (4) (R¹ =phenylacetamido, R² =H, R³=diphenylmethyl, R⁴ =benzothiazol-2-yl, R⁸ =trifluoromethyl, m=0)instead of the compound of the formula (4) (R¹ =phenylacetamido, R² =H,R³ =p-methoxybenzyl, R⁴ =phenyl, R⁸ =trifluoromethyl, m=2), whereby thecorresponding compound of the formula (1) (R¹, R² R³, R⁴ and m are asdefined above, 1c) was obtained in a yield of 99%.

INDUSTRIAL APPLICABILITY

The desired useful cephem compound represented by the general formula(3) and having a broad antibacterial spectrum can be prepared by theinvention at ambient temerature (room temperature) in a high yieldwithout the necessity of preparing an organocopper reagent or the like.The invention advantageously affords the desired product withoutnecessitating special purification since the process does not involveformation of undesirable 2-cephem compounds as by-products.

We claim:
 1. A process for preparing a cephem compound represented bythe formula (3) characterized in that an allenyl-β-lactam compoundrepresented by the formula (1) is reacted at a temperature of from -10°to 80° C. with an organotin compound represented by the formula (2) inthe presence of a monovalent copper salt ##STR6## wherein R¹ is ahydrogen atom, halogen atom, amino or protected amino,R² is a hydrogenatom, halogen atom, lower alkoxyl, lower acyl, lower alkyl, lower alkylhaving hydroxyl or protected hydroxyl as a substituent, hydroxyl orprotected hydroxyl, or R¹ and R² form=0 when taken together, R³ is ahydrogen atom or carboxylic acid protecting group, R⁴ is phenyl,naphthyl, a nitrogen-containing aromatic heterocyclic group selectedfrom the group consisting of thiazol-2-yl, thiadiazol-2-yl,benzothiazol-2-yl, oxazol-2-yl, benzoxazol-2-yl, imidazol-2-yl,benzoimidazol-2-yl, pyrimidinyl, and pyridyl, wherein said phenylnaphthyl or nitrogen-containing aromatic heterocyclic group may have atleast one substituent selected from the group consisting of halogen,hydroxyl, nitro, cyano, phenyl, naphthyl, lower alkyl, amino, mono loweralkylamino, di lower alkylamino, mercapto, R⁷ S--, formyl, formyloxy, R⁷COO--, R⁷ CO--, R⁷ O--, R⁷ OCO--, and carboxyl, and m is 0 or 2,

    (R.sup.5).sub.n --Sn(R.sup.6).sub.4--n                     ( 2)

wherein R⁵ is alkenyl, phenyl, naphthyl, a nitrogen-containing aromaticheterocyclic group selected from the group consisting of thiazol-2-yl,thiadiazol-2-yl, benzothiazol-2-yl, oxazol-2-yl, benzoxazol-2-yl,imidazol-2-yl, benzoimidazol-2-yl, pyrimidinyl, and pyridyl, whereinsaid alkenyl, phenyl, naphthyl or nitrogen-containing aromaticheterocyclic group may have at least one substituent selected from thegroup consisting of halogen, hydroxyl, nitro, cyano, phenyl, naphthyl,lower alkyl, amino, mono lower alkylamino, di lower alkylamino,mercapto, R⁷ S--, formyl, formyloxy, R⁷ COO--, R⁷ CO--, R⁷ O--, R⁷OCO--, and carboxyl, R⁶ is lower alkyl, R⁷ is C₁₋₋₄ alkyl, phenyl ornaphthyl, and n is 1 or 2, ##STR7## wherein R¹, R², R³ and R⁵ are thesame as defined above.
 2. A process as defined in claim 1 wherein themonovalent copper salt is cuprous chloride, cuprous bromide or cuprousiodide.
 3. A process as defined in claim 1, wherein from 1 to 3 moles ofthe organotin compound is reacted per mole of the allenyl-β-lactamcompound.
 4. A process as defined in claim 1, wherein from 0.5 to 10moles of the monovalent copper salt is present per mole of theallenyl-β-lactam compound.
 5. A process as defined in claim 4, whereinfrom 1 to 3 moles of the monovalent copper salt is present per mole ofthe allenyl-β-lactam compound.
 6. A process as defined in claim 1,wherein the allenyl-β-lactam is reacted with the organotin compound at atemperature of from 0° to 50° C.